This application requests $600,000 for an upgrade of the 15 year-old Bruker DRX-600 NMR Spectrometer at the Tufts Biological NMR Center, a facility of the Tufts University School of Medicine in Boston. Retaining the Bruker UltraShield 600 magnet and vibration stand, the upgrade will completely replace the DRX console electronics with a new generation Avance III HDTM 600 high performance digital NMR console equipped with four channels. The faster electronics are required in order to run the latest pulse programs, and features such as non-uniform sampling (NUS) which can lead to a doubling of the sensitivity in 3D and 4D experiments. To obtain these advantages, the obsolete SGI O2 workstation and XWINNMR 3.6 software must also be replaced with a Linux workstation running Bruker's latest TopSpin 3.2 software package for data acquisition and processing. In addition, the former triple resonance TXI 5 mm probe will be replaced with a Prodigy triple resonance 5 mm cryoprobe operating the coil and preamplifier at liquid nitrogen temperature, leading to an additional factor of 2.5 for proton inverse detection. Instrument reliability and maintainability wll also increase markedly, as it has become increasingly difficult to obtain parts and expertise for our existing DRX-600 at Bruker. Ease of operation will be greatly enhanced by the autoshim and autotune features of the proposed new system. Access to high-field NMR spectrometers has always been limited both nationwide and specifically in the Boston area, which restricts the ability of scientists to tackle a number of challenging areas of biomedical research. The upgraded 600 MHz spectrometer will allow faster data collection, with higher quality, particularly for larger proteins, and with less instrument down time. This will drastically increase the capacit of the NMR facility. It will also enable users to study the structure and dynamics of proteins and complexes with high molecular weights and/or limited solubility, which are not possible on the current instrument due to its lack of sensitivity. The research of the six major users includes the following NIH-funded project areas that will directly benefit from a state-of-the-art 600 MHz NMR spectrometer: 1) Structural determination of novel therapeutic peptides and proteins. 2) Characterization of protein-protein and protein-drug interfaces 3) Uncovering metabolic vulnerabilities in cancer. Three additional minor users are NIH-supported, while obtaining this instrument will help an additional five users be more competitive to obtain NIH support. Use of the upgraded 600 MHz NMR spectrometer by other researchers will be encouraged and instrument time will be made available for them. In summary, the requested upgrade and cryogenic probe for a 600 MHz NMR spectrometer will be a valuable asset for the biomedical research community at Tufts University and the Boston area. It will immediately impact active NIH-funded research in multiple areas, in particular cancer, cardiovascular disease, diabetes, and infectious disease.